BACKGROUND Axonal injury of the optic nerve (ON) is involved in various ocular diseases, such as glaucoma and traumatic optic neuropathy, which leads to apoptotic death of retinal ganglion cells (RGCs) and loss of vision. Caspases have been implicated in RGC pathogenesis. However, the role of caspase-7, a functionally unique caspase, in ON injury and RGC apoptosis has not been reported previously. The purpose of this study is to evaluate the role of caspase-7 in ON injury-induced RGC apoptosis. RESULTS C57BL/6 (wildtype, WT) and caspase-7 knockout (Casp7(-/-)) mice were used. We show that ON crush activated caspase-7 and calpain-1, an upstream activator of caspase-7, in mouse RGCs, as well as hydrolysis of kinectin and co-chaperone P23, specific substrates of caspase-7. ON crush caused a progressive loss of RGCs to 28 days after injury. Knockout of caspase-7 partially and significantly protected against the ON injury-induced RGC loss; RGC density at 28 days post ON crush in Casp7(-/-) mice was approximately twice of that in WT ON injured retinas. Consistent with changes in RGC counts, spectral-domain optical coherence tomography analysis revealed that ON crush significantly reduced the in vivo thickness of the ganglion cell complex layer (including ganglion cell layer, nerve fiber layer, and inner plexiform layer) in the retina. The ON crush-induced thinning of retinal layer was significantly ameliorated in Casp7(-/-) mice when compared to WT mice. Moreover, electroretinography analysis demonstrated a decline in the positive component of scotopic threshold response amplitude in ON crushed eyes of the WT mice, whereas this RGC functional response was significantly higher in Casp7(-/-) mice at 28 days post injury. CONCLUSION Altogether, our findings indicate that caspase-7 plays a critical role in ON injury-induced RGC death, and inhibition of caspase-7 activity may be a novel therapeutic strategy for glaucoma and other neurodegenerative diseases of the retina.

中文翻译：

---

Caspase-7：视神经损伤引起的视网膜神经节细胞死亡的关键介质。

背景技术视神经（ON）的轴突损伤涉及各种眼疾病，例如青光眼和外伤性视神经病变，其导致视网膜神经节细胞（RGC）凋亡死亡和视力丧失。胱天蛋白酶与RGC的发病机理有关。但是，功能上独特的半胱天冬酶caspase-7在ON损伤和RGC凋亡中的作用尚未见报道。本研究的目的是评估caspase-7在ON损伤诱导的RGC凋亡中的作用。结果使用C57BL / 6（野生型，WT）和caspase-7基因敲除（Casp7（-/-））小鼠。我们显示，在小鼠RGCs上，ON Crush激活了caspase-7和calpain-1，caspase-7的上游激活剂，以及角蛋白和co-伴侣P23，caspase-7的特定底物的水解。ON压伤在受伤后28天导致RGC逐渐丢失。caspase-7的敲除部分且显着地保护了ON损伤引起的RGC丢失；Casp7（-/-）小鼠ON压迫后28天的RGC密度大约是WT ON损伤的视网膜的RGC密度的两倍。与RGC计数的变化一致，光谱域光学相干断层扫描分析显示ON压碎显着减少了视网膜中神经节细胞复合物层（包括神经节细胞层，神经纤维层和内部丛状层）的体内厚度。与WT小鼠相比，Casp7（-/-）小鼠的ON挤压诱导的视网膜层变薄得到了明显改善。此外，视网膜电图分析显示，在WT小鼠的ON压迫眼中，暗疮阈值反应幅度的正向分量有所下降，而CGC7（-/-）小鼠在受伤后28天的RGC功能反应明显更高。结论总的来说，我们的发现表明caspase-7在ON损伤引起的RGC死亡中起关键作用，而caspase-7活性的抑制可能是青光眼和其他视网膜神经退行性疾病的一种新型治疗策略。